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In patients with head and neck cancer presenting with low hemoglobin levels, poor locoregional control and disease-free survival rates after radiotherapy can be corrected by use of the ARCON hypoxia-modulating regimen, in which accelerated radiotherapy is combined with carbogen and the water-soluble vitamin nicotinamide. That was the conclusion of a study reported at the European Society for Radiotherapy and Oncology and World Congress of Brachytherapy joint meeting in Barcelona.

“ARCON [accelerated radiotherapy, carbogen, and nicotinamide] is the first treatment to demonstrate improved outcomes in terms of locoregional control and disease-free survival in anemic patients,” said investigator Geert O.R.J. Janssens, MD, a radiation oncologist at Radboud University Nijmegen Medical Centre in The Netherlands.

He explained that anemia renders tumors more hypoxic, which then makes the tumors more aggressive, with more lymph node involvement and more distant metastases.

Several previous attempts to correct the problem failed. For example, he noted that transfusion of red blood cells did not improve outcome in a study reported last year (Hoff CM et al: Results from the randomized DAHANCA 5 & 7 trials. Acta Oncologica 2011;50:1006–1014), and there are strong suggestions that even though erythropoietin increases hemoglobin levels, there is an overall negative influence on outcome (Lambin P et al: The Cochrane Collaboration, 2009).

Janssens and his colleagues hypothesized that carbogen—a mixture of carbon dioxide and oxygen—could influence the range of hypoxia via diffusion and that the nicotinamide would open the vessel.

“If there is more oxygen, you can have a greater effect for radiation. Lack of oxygen makes the tumor more aggressive so more oxygen makes it less aggressive,” he said in an interview after the meeting.

To test the hypothesis, the researchers recruited 345 patients with cT2–4 squamous cell laryngeal cancer to a randomized trial. All patients received accelerated radiotherapy (AR), in which two fractions per day are administered during the last week of treatment to reduce the overall length of treatment. Then, 171 patients also received ARCON, which consisted of taking nicotinamide tablets (60 mg/kg) 60 to 90 minutes prior to treatment and inhaled carbogen during radiotherapy.

Accelerated radiation was given to a total dose of 68 Gy within 36 to 38 days on the primary tumor and the pathological lymph nodes. To limit the risk of late laryngeal necrosis, a dose reduction to 64 Gy to the larynx was given with ARCON. Hemoglobin levels were measured before, weekly during, and after radiotherapy.

Pre-irradiation hemoglobin levels were below normal—i.e., less than 7.5 mmol/L in females and less than 8.5 mmol/L in males—in 27 of 173 patients in the AR-only group and in 27 of 167 ARCON patients.

Results

After a median follow-up of 44 months, the local tumor control rate at five years was 78% for patients receiving AR versus 79% for the ARCON group, with corresponding larynx preservation rates of 84% and 87%. The five-year regional control rate was significantly better with ARCON (93%) compared with AR (86%).

The improvement in regional control was specifically observed in patients with hypoxic tumors and not in patients with well-oxygenated tumors (100% versus 55%), the researchers reported.

In addition, patients treated with accelerated radiotherapy alone who had normal hemoglobin levels before treatment had significantly better control of the cancer at its primary site (76% as opposed to 56%), disease-free survival (72% and 48%, respectively), and metastasis-free survival (90% and 70%) than those with low Hb levels.

“However, when we looked at the ARCON group, in cases where the patients had low Hb levels before treatment, we found that ARCON improved control of the cancer at its primary site and improved disease-free and metastasis-free survival, so that the differences between them and patients with normal Hb levels were no longer significant,” Janssens said.

In fact, the difference in the local control rate between this low-Hb group and the normal-Hb accelerated-radiotherapy-alone group was only 1% (81% in the ARCON group vs 82% in the AR-only group). The disease-free survival rates were 77% in the ARCON group and 70% in the AR group, and the metastasis-free survival rates were 93% and 89%, respectively.

However, patients with low pretreatment hemoglobin levels still had a worse overall survival regardless of which treatment they received. He said that this is most likely due to the fact that many patients with head and neck cancer also have other health problems that cannot be treated by radiotherapy. AR and ARCON produced equal levels of toxicity.

Why Worked When Previous Approaches Failed?

Asked why he thought the new approach worked where others had failed, Janssens said, “We know that a decrease in Hb levels is associated with a reduced sensitivity to radiotherapy and that this can switch the tumor microenvironment into a more aggressive subtype with a higher risk of loco-regional failure and of the development of distant metastases.

“The lack of success with transfusion of red blood cells or erythropoietin suggests underlying adaptive mechanisms. Accelerated radiotherapy to counteract tumor cell repopulation during radiotherapy, combined with carbogen and nicotinamide, administered immediately before irradiation to increase the oxygen level, ensures that adaptive mechanisms cannot erode the effect, and this is probably the key to success of the ARCON regime in patients with low HB levels at presentation.”

ESTRO President: ‘Important Study’

Commenting in a news release, ESTRO President Vincenzo Valentini, MD, said, “We know that the degree of oxygenation of tumors in laryngeal cancer patients is directly related to the damage that can be caused to them by radiotherapy. This important study shows that, in patients with low hemoglobin levels, it is possible to reoxygenate the tumor by using the simple and cost-effective ARCON regime, and therefore increase the effectiveness of radiation treatment.”

Asked for his perspective for this article, Robert S. Lavey, MD, MPH, Senior Member in the Department of Radiation Oncology at Moffitt Cancer Center, noted that transfusions of red blood cells and erthropopoeitin are not the only methods that have failed to overcome the problem of low hemoglobin levels in these patients. For example, he said, researchers have tried restricting oxygen flow to normal tissue to equalize them and using hypoxic cell-sensitizing agents to make the hypoxic cells more sensitive to radiation.

But those approaches also met with little success, he said. “ARCON stands out for demonstrating efficacy without significant toxicity in a randomized trial of bladder cancer and now, with this new study, in head and neck cancer as well.

“This is an important trial that can be used to change clinical practice,” Lavey said, noting, though, that accelerated radiation is not standard of care in the U.S.

He said that the method could easily be incorporated in any radiation oncology department. There are still a few questions to be addressed, he added, such as whether the approach would work if the radiation regimen is not accelerated.